Novel approaches to create selective antibody biocatalysts to speed up chemical reactions have made much progress. It is now time to apply the recent developments in catalytic antibody design to important human clinical toxicological problems. For example, it is clear that an anti- cocaine antibody with selective esterolytic action could lead to the detoxication of cocaine. The central hypothesis of our work is that a "transition state mimic" hapten of cocaine hydrolysis elicits an immune response that affords anti-cocaine catalytic esterolytic activity. Using chemical, immunological and molecular approaches we have developed several unique methods for the production of esterolytic catalytic antibodies. The studies are divided into 3 major sections: (1) Chemical synthesis of "transition state analogs" of cocaine ester hydrolysis, (2) Novel selection strategies to identify monoclonal anti-cocaine catalytic esterolytic and non-esterolytic high affinity antibodies, and (3) Cloning, sequencing and expression of active anti-cocaine esterolytic antibody domains. The specific aims of section l are to synthesize transition state mimics of cocaine hydrolysis and to procure esterolytic and non- esterolytic antibodies. The specific aims of section 2 are: a) to select esterolytic catalytic and "tight-binding" anti-cocaine monoclonal antibodies and characterize the kinetic properties, substrate specificity and protein structural features. The specific aims of section 3 are: a) to isolate and sequence the cDNA encoding the catalytic antibodies identified in Sections 1 and 2 and to express the cDNA of the variable active fragments in E. coli and b) to characterize the kinetics, substrate specificity and structural properties of the expressed fragments. The parallel in vitro-in vivo experimental design will permit the direct testing of the central hypothesis. The procurement of anti-cocaine catalytic antibodies and active anti-cocaine recombinant antibody fragments provides an opportunity to experimentally answer important basic molecular questions which have direct benefits for human cocaine detoxication.